PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a deadly liver cancer which has been rising in incidence over several decades. Unfortunately, immunomodulatory therapies which have revolutionized clinical paradigms in many other cancers, have thus far demonstrated only limited efficacy in a small fraction of ICC patients. We hypothesize that a better understanding of the mechanisms by which this disease evades immune recognition will allow for the development of therapeutic strategies that improve antitumoral immunity. To address these questions, we have developed the first and only genetically-engineered mouse model (GEMM) of isocitrate dehydrogenase (IDH) mutant ICC, which represents the most common genetic subset of ICC (20-25% of patients). While pharmacologic inhibitors of mutant IDH (IDH*) are currently being evaluated in clinical trials and appear to provide some clinical benefit with minimal toxicity, these effects are only transient, suggesting that combinatorial strategies are needed to induce durable remissions. Intriguingly, recent reports have suggested that IDH* may also suppress immune responses, thus contributing to immune evasion. For instance, the presence of IDH* in a syngeneic model of glioma resulted in a dramatic suppression of chemotaxis and immune cell infiltration into tumors. Moreover, the upregulation of immune-response related genes in patients with IDH* ICC seems to correlate with clinical response. Here, we propose to use our GEMM of IDH* ICC to characterize the impact of IDH* on immune surveillance in the normal and injured murine liver. We will then determine whether IDH* inhibition may enhance immune cell infiltration or activation in established IDH* ICC tumors. These preliminary studies will pave the way for future mechanistic work where we functionally interrogate the role of individual cell types and cytokines and explore how IDH* subverts their normal activity, with the ultimate goal of identifying therapeutic strategies that may effectively combine IDH* inhibition with immunomodulatory therapy for ICC and other IDH* cancers.